Neuronal receptive fields are modified by experience through plastic mechanisms like long-term potentiation (LTP) and depression (LTD). It is clear, however, that experience-induced plasticity not only depends on the patterns of sensory input, but also on the level of neuromodulatory signals related to the behavioral state of the animal. Recent evidence reveals that neuromodulator receptors provide a robust control of the polarity of spike timing dependent plasticity (STDP) in the primary visual cortex (V1) in vitro (Seol GH et al., 2007). For example, a1-adrenoreceptors (a1-AR), which are coupled to phospholipase C, gate the expression of associative LTD and suppress LTP (Treviño M. and Kirkwood A., 2008-S-102674-SfN). Here, we explored whether a1-AR neuromodulation of plasticity is operational in V1 of adult mice in vivo. We found that systemic application of a1-AR agonists in conjunction with 1 hr of visual grating stimulation depresses active synapses from layer 2/3 pyramidal cells ex vivo. Notably, this manipulation also produced a rapid decrease of the visual acuity of the mice, a sensory discrimination threshold that depends on V1 processing. Plasticity in visual performance with this task is orientation-specific because it is not transferred if visual stimulation during neuromodulator action is orthogonal to testing orientation (an arrangement that segregates activated from non-activated synapses), and is also absent when visual experience is provided under global blockage of NMDARs. Therefore, we propose that neuromodulators enable and control Hebbian plasticity of active synapses in V1 leading to a permanent change in the way specific visual information is transferred between and within superior cortical layers.